KR20100014512A - Novel polymorphs of erlotinib hydrochloride and method of preparation - Google Patents

Novel polymorphs of erlotinib hydrochloride and method of preparation Download PDF

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KR20100014512A
KR20100014512A KR1020097019720A KR20097019720A KR20100014512A KR 20100014512 A KR20100014512 A KR 20100014512A KR 1020097019720 A KR1020097019720 A KR 1020097019720A KR 20097019720 A KR20097019720 A KR 20097019720A KR 20100014512 A KR20100014512 A KR 20100014512A
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ethynylphenyl
bis
quinazolinamine
erlotinib
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라마나드함 제이요티 프라사드
부장가 라오 아딥하틀라 칼리 사트야
난나파네니 벤카이아흐 쵸우다리
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낫코 파마 리미티드
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Abstract

The present invention relates to three novel crystalline forms of Erlotinib hydrochloride and method of preparation thereof. Erlotinib hydrochloride is N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride of formula-(I). The present invention provides stable novel crystalline forms of Erlotinib hydrochloride designated as Form-M, Form-N and Form-P, and processes for the preparation of the same. Erlotinib hydrochloride can be used as medicament for the treatment of hyperproliferative disorders, such as cancers, in humans.

Description

엘로티닙 하이드로클로라이드의 신규한 다형체 및 제조방법 {NOVEL POLYMORPHS OF ERLOTINIB HYDROCHLORIDE AND METHOD OF PREPARATION}Novel polymorph and preparation method of erlotinib hydrochloride {NOVEL POLYMORPHS OF ERLOTINIB HYDROCHLORIDE AND METHOD OF PREPARATION}

본 발명은 화학식 1의 엘로티닙 하이드로클로라이드(erlotenib hydrochloride)의 3가지의 신규 다형체 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)에 관한 것이다. 엘로티닙은 N-(3-에티닐페닐)-6,7-비스(2-메톡시 에톡시)-4-퀴나졸린아민(N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine)이고, EGF 수용체(epidermal growth factor receptor; EGFR)와 같은 옹코진(oncogenic) 및 프로토옹코진(protooncogenic) 단백질 티로신 카이네이즈(protein tyrosine kinases)의 erbB군(erbB family)에 대한 저해제(inhibitor)이다. 따라서, 인체 내에서 암과 같은 증식성 질환(prolifirative disorders)의 치료에 유용하며, 하이드로클로라이드 염(I)으로 종종 사용된다.The present invention relates to three novel polymorphs, Form-M, Form-N, and Form-P (Form-P) of erlotenib hydrochloride of formula (I). . Erlotinib is N- (3-ethynylphenyl) -6,7-bis (2-methoxy ethoxy) -4-quinazolinamine (N- (3-ethynylphenyl) -6,7-bis (2-methoxy ethoxy) -4-quinazolinamine) and for the erbB family of oncogenic and protocogenic protein tyrosine kinases, such as the epidermal growth factor receptor (EGFR). Inhibitor. Therefore, it is useful for the treatment of prolifirative disorders such as cancer in the human body, and is often used as a hydrochloride salt (I).

Figure 112009057941199-PCT00001
Figure 112009057941199-PCT00001

배경기술Background

N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민의 화학명을 가지는 엘로티닙은 PCT 공개공보 제 WO 96/30347호 및 대응 특허 US 5,747,498(1998)에서 보고되었다. 비록, 이의 하이드로클로라이드 염에 대한 제조방법이 위 특허에서 언급되어 있을지라도, 그것의 다형체 및 이들의 특성이 대하여는 언급되어 있지 않다. 녹는점을 제외하고는 그것의 고체 상태 특성에 대하여 위 특허에 어느 것도 개시되어 있지 않다.Erlotinib having the chemical name of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine is disclosed in PCT Publication WO 96/30347 and the corresponding patents US 5,747,498. (1998). Although a process for the preparation of its hydrochloride salts is mentioned in the above patents, their polymorphs and their properties are not mentioned. Except for the melting point, none of the above patents disclose their solid state properties.

또한, PCT 공개공보 제 WO 01/34574 호 및 대응 특허 US 6,900,221 (2005)도 엘로티닙 HCl의 다형체-A 및 B를 설명하고 있으며, 다형체 'B'는 열역학적으로 더 안정함을 언급하고 있다. 위 특허는 US 5,747,498의 프로덕트가 다형체 A 및 B의 혼합물임을 또한 밝혀내었다. 다형체-A가 존재하지 않는 엘로티닙 HCl의 순수 다형체-B를 제조하는 방법 또한 US 6,900,221에서 클레임(claim)되어 있다. 결정형 A 및 B 둘 다의 분말 XRD 데이터가 위 특허에 개시되어 있다.PCT Publication WO 01/34574 and the corresponding patent US Pat. No. 6,900,221 (2005) also describe polymorphs-A and B of erlotinib HCl, mentioning that polymorph 'B' is thermodynamically more stable. . The patent also revealed that the product of US 5,747,498 is a mixture of polymorphs A and B. A process for preparing pure polymorph-B of erlotinib HCl free of polymorph-A is also claimed in US Pat. No. 6,900,221. Powder XRD data of both Forms A and B are disclosed in this patent.

국제 출원 PCT/EP2004/001244에 대응하는 특허 WO 2004/072049는 신규한 다형체 E 및 그것의 DSC와 XRD 특징을 개시하고 있으며, 다형체 A에 비해 향상된 안정성을 나타내고 있다. 그러나, 이 다형체 E는 매우 가연성이 높고 환경에 위험한 (α,α,α)-트리플루오로톨루엔)((α,α,α)-trifluorotoluene)) 중에서 제조된다. 또한, 값이 비싼 용매이며, 산업적 규모에서 다루기 용이하지 않다.Patent WO 2004/072049, corresponding to the international application PCT / EP2004 / 001244, discloses a novel polymorph E and its DSC and XRD features and shows improved stability compared to polymorph A. However, this polymorph E is prepared in highly flammable and environmentally dangerous (α, α, α) -trifluorotoluene) ((α, α, α) -trifluorotoluene). It is also an expensive solvent and not easy to handle on an industrial scale.

발명의 요약Summary of the Invention

엘로티닙 HCl의 안정한 다형체 조사에 대한 끊임없는 노력이 형체-M(Form-M), 형체-N(Form-N) 및 형체-P(Form-P)로 지정된 3개의 안정한 신규 결정형에 대한 발명을 낳았다. 3가지의 신규 결정형 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)는 놀랍게도 예상치 못하게 실온(30~35℃)에서 고체 상태로 매우 안정하고, 60~120℃의 더 높은 온도에서도 매우 안정하다. 상기 언급된 신규 다형체는 저렴하면서도 시판되고 있는 이소프로판올, 메탄올 및 메틸렌 클로라이드와 같은 용매를 적용하여 제조될 수 있으며, 이들 용매는 큰 규모의 제조에도 적합하다. 이에, 신규한 엘로티닙 HCl의 형체-M은 메탄올 중의 엘로티닙 베이스(base)를 이소프로판올 HCl(isopropanolic HCl)과 함께 처리하여 제조된다. 유사하게, 상기 신규 형체-N은 이소프로판올 중의 엘로티닙 베이스를 이소프로판올 HCl로 처리하여 제조되고, 형체-P는 메틸렌 클로라이드 중의 엘로티닙 베이스를 이소프로판올 HCl과 함께 처리하여 제조된다. 상기 3가지의 신규 형태, 엘로티닙 HCl의 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)는 분말 XRD 패턴을 특징으로 하며, 고체 상태로 매우 안정하다.Incessant efforts to investigate stable polymorphs of erlotinib HCl have led to the invention of three stable new crystalline forms designated as Form-M (Form-M), Form-N (Form-N) and Form-P (Form-P). Gave birth to. Three new crystalline Form-M, Form-N and Form-P are surprisingly very stable in solid state at room temperature (30-35 ° C.), Very stable even at higher temperatures of 60-120 ° C. The novel polymorphs mentioned above can be prepared by applying solvents such as isopropanol, methanol and methylene chloride, which are inexpensive and commercially available, and these solvents are also suitable for large scale preparation. Thus, the new Form-M of erlotinib HCl is prepared by treating an erlotinib base in methanol with isopropanol HCl (isopropanolic HCl). Similarly, the new form-N is prepared by treating erlotinib base in isopropanol with isopropanol HCl and the form-P is prepared by treating erlotinib base in methylene chloride with isopropanol HCl. The three new forms, Form-M, Form-N, and Form-P of erlotinib HCl, are characterized by a powder XRD pattern and are very solid. Stable.

따라서, 본 발명의 주요 목적은 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)로 지정된 엘로티닙 HCl의 안정한 신규 결정형을 제공하는 것이다.It is therefore a primary object of the present invention to provide stable new crystalline forms of erlotinib HCl, designated as Form-M, Form-N, and Form-P.

본 발명에 따른 하나의 목적은 형체-M(Form-M), 형체-N(Form- N) 및 형체- P(Form-P)로 지정된 엘로티닙 HCl의 안정한 신규 결정형의 제조방법을 제공하는 것이다.One object according to the present invention is to provide a method for preparing a stable novel crystalline form of erlotinib HCl, designated as Form-M, Form-N, and Form-P. .

따라서, 본 발명은 하기에 주어진 특징을 가지는 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)로 지정된 엘로티닙 HCl의 안정한 신규 결정형을 제공한다:Accordingly, the present invention provides a stable novel crystalline form of erlotinib HCl, designated Form-M, Form-N, and Form-P having the characteristics given below:

X-레이 분말 회절 패턴(X-ray Powder Diffraction Pattern):X-ray Powder Diffraction Pattern:

(i) 형체-M(Form-M): 도 1에 나타난 바와 같이 2θ 스케일 상에서 약 6.2, 7.9, 9.6, 11.4, 12.5, 13.4, 14.7, 15.7, 17.0, 17.6, 19.2, 20.2, 20.7, 21.1, 21.9, 22.4, 23.0, 23.9, 24.4, 25.1, 25.9, 26.8, 29.0, 29.7, 31.7, 32.7, 34.8, 40.2의 특징적인 대표적 피크를 가짐. (i) Form-M: about 6.2, 7.9, 9.6, 11.4, 12.5, 13.4, 14.7, 15.7, 17.0, 17.6, 19.2, 20.2, 20.7, 21.1, on 2θ scale as shown in FIG. Has characteristic representative peaks of 21.9, 22.4, 23.0, 23.9, 24.4, 25.1, 25.9, 26.8, 29.0, 29.7, 31.7, 32.7, 34.8, 40.2.

(ii) Form-N: 도 2에 나타난 바와 같이 2θ 스케일 상에서 약 5.56, 9.72, 11.25, 12.82, 18.84, 19.38, 21.01, 22.74, 23.46, 24.23, 25.34, 26.70, 29.17, 32.77, 37.21, 39.96, 45.66의 특징적인 대표적 피크를 가짐. (ii) Form-N: about 5.56, 9.72, 11.25, 12.82, 18.84, 19.38, 21.01, 22.74, 23.46, 24.23, 25.34, 26.70, 29.17, 32.77, 37.21, 39.96, 45.66 on 2θ scale as shown in FIG. Has a characteristic peak of.

(iii) Form-P: 도 3에 나타난 바와 같이 2θ 스케일 상에서 2.97, 5.80, 6.36, 9.97, 10.54, 11.48, 15.00, 15.80, 16.64, 17.11, 17.62, 18.15, 18.58, 19.06, 19.78, 20.74, 22.14,(iii) Form-P: 2.97, 5.80, 6.36, 9.97, 10.54, 11.48, 15.00, 15.80, 16.64, 17.11, 17.62, 18.15, 18.58, 19.06, 19.78, 20.74, 22.14, on 2θ scale as shown in FIG.

22.96, 23.72, 24.45, 25.67, 26.40, 27.30, 28.14, 28.76, 29.44, 30.15, 30.82, 32.21, 32.95, 33.99, 34.59, 40.49, 40.64, 42.02, 43.87의 특징적인 대표적 피크를 가짐. With characteristic representative peaks of 22.96, 23.72, 24.45, 25.67, 26.40, 27.30, 28.14, 28.76, 29.44, 30.15, 30.82, 32.21, 32.95, 33.99, 34.59, 40.49, 40.64, 42.02, 43.87.

본 발명의 다른 특징에 따르면, 상기 언급된 특징을 가지는 화학식-(I)의 엘로티닙 하이드로클로라이드의 신규 결정형 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)의 제조방법을 제공하며,According to another feature of the invention, novel crystalline Form-M (Form-M), Form-N (Form-N) and Form-P (Form) of erlotinib hydrochloride of formula (I) having the above-mentioned characteristics -P) provides a manufacturing method,

Figure 112009057941199-PCT00002
Figure 112009057941199-PCT00002

(i) 드라이 메탄올에 엘로티닙 베이스(국제출원 공개 제 WO 2007/060691호에 주어진 프로세스에 따라 제조됨)를 용해하고, 메탄올 또는 이소프로판올 중 드라이 HCl 가스 용액(a solution of dry HCl gas in methanol or isopropanol)을 첨가하는 것을 포함한다. 이에 따라 제조된 엘로티닙 HCl의 결정은 건조되고, 형체-M(Form-M)으로 지정한다. (i) dissolving erlotinib base (prepared according to the process given in WO 2007/060691) in dry methanol, and a solution of dry HCl gas in methanol or isopropanol ) Is added. Crystals of erlotinib HCl thus prepared are dried and designated Form-M.

(ii) 드라이 이소프로판올에 엘로티닙 베이스(국제출원 공개 제 WO 2007/060691호에 주어진 프로세스에 따라 제조됨)를 용해하고, 이소프로판올 중 드라이 HCl 가스 용액을 첨가하는 것을 포함한다. 상기 엘로티닙 HCl의 결정을 필터하고, 건조하여, 형체-N(Form- N)으로 지정한다. (ii) dissolving erlotinib base (prepared according to the process given in WO 2007/060691) in dry isopropanol and adding a dry HCl gas solution in isopropanol. The crystals of erlotinib HCl are filtered, dried, and designated Form-N.

(iii) 드라이 메틸렌 클로라이드에 엘로티닙 베이스(국제출원 공개 제 WO 2007/060691호에 주어진 프로세스에 따라 제조됨)를 용해하고, 이소프로판올 중 드 라이 HCl 가스 용액을 첨가하는 것을 포함한다. 상기 엘로티닙 HCl의 결정을 필터하고, 건조하여, 형체- P (Form- P)로 지정한다. (iii) dissolving erlotinib base (prepared according to the process given in WO 2007/060691) in dry methylene chloride and adding a solution of dry HCl gas in isopropanol. The crystals of erlotinib HCl are filtered, dried and designated Form-P.

하기 실시예들은 본 발명의 과정을 구체적으로 설명하기 위한 용도로 주어진 것이며, 따라서 발명의 범위 또는 범주를 제한하는 것으로 고려되지 않는다.The following examples are given for the purpose of illustrating the process of the invention in detail and are therefore not to be considered as limiting the scope or scope of the invention.

실시예-1Example-1

엘로티닙 HCI 다형체-M의 제조:Preparation of Elotinib HCI Polymorph-M:

기계식 교반기(mechanical stirrer), 온도계 소켓(thermometer socket), 리플럭스 콘덴서(reflux condenser)등이 제공된 2리터의 4구 둥근바닥 플라스크(four necked round-bottomed flask)에 1340 mL의 메탄올을 넣은 다음, 60 g의 엘로티닙 베이스(국제출원 공개 제 WO 2007/060691호의 실시예-(I)에 주어진 프로세스에 따라 제조됨)를 넣었다. 반응 매스(reaction mass)는 약 40℃로 데워져, 엘로티닙 베이스가 완전히 용해되도록 하였다. 이러한 반응 매스에 탄소 처리(carbon treatment)하고, 여과액은 다른 2리터의 4구 플라스크로 옮겼다. 이러한 용액에 이소프로판올 HCl(isopropanolic HCl; 100% HCl 함량이 6.12g)이 1로트(lot)로 첨가되고, 반응 매스는 30-35℃에서 약 90분간 교반하고, 필터링하였다. 생성물은 새로운 메탄올로 워싱하고, 젖은 케이크(cake)를 건조시켜 백색 결정성 분말과 같 은 55.2g의 엘로티닙 하이드로클로라이드를 획득하였다.1340 mL of methanol was added to a 2-liter four necked round-bottomed flask provided with a mechanical stirrer, thermometer socket and reflux condenser. g of erlotinib base (prepared according to the process given in Example- (I) of WO 2007/060691) was charged. The reaction mass was warmed to about 40 ° C. to allow the erlotinib base to dissolve completely. This reaction mass was carbon treated and the filtrate was transferred to another two liter four-neck flask. To this solution isopropanol HCl (isopropanolic HCl; 6.12 g of 100% HCl content) was added in one lot, the reaction mass was stirred at 30-35 ° C. for about 90 minutes and filtered. The product was washed with fresh methanol and the wet cake was dried to give 55.2 g of erlotinib hydrochloride such as white crystalline powder.

XRPD: 형체-M (도 1)XRPD: Shape-M (FIG. 1)

실시예-2Example-2

엘로티닙 HCI 다형체-N의 제조:Preparation of Erlotinib HCI Polymorph-N:

기계식 교반기(mechanical stirrer), 온도계 소켓(thermometer socket), 리플럭스 콘덴서(reflux condenser)등이 제공된 1리터의 4구 둥근바닥 플라스크(four necked round-bottomed flask)에 325 mL의 이소프로필 알콜을 넣은 다음, 25.0 g의 엘로티닙 베이스(국제출원 공개 제 WO 2007/060691호의 실시예-(I)에 주어진 프로세스에 따라 제조됨)를 70-75℃에서 넣어, 엘로티닙 베이스가 용매 중에서 완전히 용해되도록 하였다. 이후, 탄소 처리(carbon treatment)하고, 여과액은 다른 1리터의 4구 플라스크로 옮겨져, 모든 필요한 부속물을 제공하였다. 이러한 용액에 이소프로폰올 HCl(isoproponolic HCl; 100% HCl 함량이 2.548 g)이 60-65℃에서 1로트(lot)로 첨가되고, 이 온도에서 약 1시간 유지하였다. 반응 매스는 실온으로 냉각하여 필터링하였다. 생성물은 새로운 이소프로필 알콜로 워싱하고, 건조시켜 백색 결정성 분말과 같은 25.0 g의 엘로티닙 하이드로클로라이드를 획득하였다.325 mL of isopropyl alcohol was added to a 1 liter four necked round-bottomed flask provided with a mechanical stirrer, thermometer socket and reflux condenser. , 25.0 g of erlotinib base (prepared according to the process given in Example- (I) of WO 2007/060691) was added at 70-75 ° C. to allow the erlotinib base to dissolve completely in solvent. After carbon treatment, the filtrate was transferred to another 1 liter four-necked flask to provide all necessary accessories. To this solution isoproponol HCl (isoproponolic HCl; 2.548 g of 100% HCl content) was added in one lot at 60-65 ° C. and maintained at this temperature for about 1 hour. The reaction mass was filtered by cooling to room temperature. The product was washed with fresh isopropyl alcohol and dried to give 25.0 g of erlotinib hydrochloride such as white crystalline powder.

XRPD: 형체-N (도 2)XRPD: Shape-N (FIG. 2)

실시예-3Example-3

엘로티닙 HCI 다형체-P의 제조:Preparation of Erlotinib HCI Polymorph-P:

기계식 교반기(mechanical stirrer), 온도계 소켓(thermometer socket), 리플럭스 콘덴서(reflux condenser)등이 제공된 3리터의 4구 둥근바닥 플라스크(four necked round-bottomed flask)에 2400 mL의 메틸렌 클로라이드를 넣은 다음, 교반하면서 120 g의 엘로티닙 베이스(국제출원 공개 제 WO 2007/060691호의 실시예-(I)에 주어진 프로세스에 따라 제조됨)를 넣었다. 반응 매스(reaction mass)는 37±1℃로 약간 데워, 엘로티닙 베이스가 용매 중에 완전히 용해되도록 하였다. 이후, 탄소 처리(carbon treatment)하였으며, 여과액은 다른 5리터의 3구 플라스크로 옮켜 기계식 교반기 및 다른 부속물을 제공하였다. 이러한 여과액에 이스프로놀 HCl(Isopronolic HCl; 100% HCl 함량이 13.90 g)이 30-35℃에서 1로트(lot)로 첨가된 다음, 반응 매스는 약 3시간 동안 리플럭스 되었다. 이후, 반응매스는 실온으로 냉각하여 필터링하였다. 생성물은 메틸렌 클로라이드로 워싱하고, 젖은 케이크(cake)를 건조시켜 백색 결정성 분말과 같은 119g의 엘로티닙 하이드로클로라이드를 획득하였다.Put 2400 mL of methylene chloride into a 3-liter four necked round-bottomed flask provided with a mechanical stirrer, thermometer socket, reflux condenser, etc. 120 g of erlotinib base (prepared according to the process given in Example- (I) of WO 2007/060691) was added with stirring. The reaction mass was slightly warmed to 37 ± 1 ° C. to allow the erlotinib base to be completely dissolved in the solvent. Thereafter, carbon treatment was performed and the filtrate was transferred to another 5 liter three-necked flask to provide a mechanical stirrer and other accessories. Isopronolic HCl (13.90 g of 100% HCl content) was added to this filtrate in one lot at 30-35 ° C., and then the reaction mass was refluxed for about 3 hours. Thereafter, the reaction mass was filtered by cooling to room temperature. The product was washed with methylene chloride and the wet cake was dried to yield 119 g of erlotinib hydrochloride as a white crystalline powder.

XRPD: 형체-P (도 3)XRPD: Shape-P (Figure 3)

실시예-4Example-4

(i) N-(3-에티닐페닐)-6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민(엘로티닙 베이스)의 제조(i) Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine (erlotinib base)

엘로티닙 베이스의 제조를 위해, 출발 매개체인 N-(3-에티닐 페닐)-6,7- 디하이드록시-4-퀴나졸린아민(N-(3-ethynyl phenyl)-6,7-dihydroxy-4-quinazolinamine)을 국제출원 공개 제 WO 2007/060691호의 실시예-(I)의 단계 (i) 내지 (v)에 기재된 프로세스로부터 제조하였다. For the preparation of erlotinib base, the starting medium N- (3-ethynyl phenyl) -6,7-dihydroxy-4-quinazolinamine (N- (3-ethynyl phenyl) -6,7-dihydroxy- 4-quinazolinamine) was prepared from the process described in steps (i) to (v) of Example- (I) of WO 2007/060691.

깨끗하고, 건조된 스테인리스 스틸 반응기에 250리터의 디메틸 포름아마이드(dimethyl formamide)를 넣은 다음, 30kg의 포타슘 카보네이트(무수; anhydrous) 및 10kg의 N-(3-에티닐 페닐)-6,7-디하이드록시-4-퀴나졸린아민을 질소 분위기 하에서 넣었다. 이 반응 혼합물에 14.0kg의 2-아이오도 에틸 메틸 에테르(2-Iodo ethyl methyl ether)를 첨가하고, 45-50℃에서 약 12시간 동안 유지하였으며, 반응은 HPLC-테스트에 의해 완료되었음을 확인하였다. 이후, 반응 매스는 실온으로 냉각하고, 매스를 센트리퓨즈(centrifuze)하여 무기염을 제거하였다.250 liters of dimethyl formamide was placed in a clean, dried stainless steel reactor, followed by 30 kg of potassium carbonate (anhydrous) and 10 kg of N- (3-ethynyl phenyl) -6,7-di Hydroxy-4-quinazolinamine was added under nitrogen atmosphere. To this reaction mixture was added 14.0 kg of 2-Iodo ethyl methyl ether and maintained at 45-50 ° C. for about 12 hours, confirming that the reaction was complete by HPLC-test. Thereafter, the reaction mass was cooled to room temperature, and the inorganic salt was removed by centrifuze the mass.

35℃ 이하에서 교반하면서, 수집된 여과액에 탈염된 물을 천천히 첨가하여 생성물이 결정화되도록 하였다. 이후 생성물을 센트리퓨즈(centrifuze)한 다음, 물로 워싱하고 젖은 케이크를 건조시켜 갈색을 띠는 황색의 결정형 고체와 같이 9.8kg(이론에 비해 69%)의 엘로티닙 베이스를 얻었다.While stirring below 35 ° C., desalted water was slowly added to the collected filtrate to allow the product to crystallize. The product was then centrifuze and then washed with water and the wet cake dried to give 9.8 kg (69% over theory) of erlotinib base as a brownish yellow crystalline solid.

순도: : 99.17% (HPLC로 측정)Purity: 99.17% (as measured by HPLC)

녹는 범위(Melting range): 151-153℃Melting range: 151-153 ℃

(ii) 엘로티닙 베이스의 정제(ii) purification of erlotinib base

하기 정제법을 채택하여 고순도의 엘로티닙 베이스를 얻었다. 깨끗하고 건도된 올글라스 반응기(All Glass Reactor)에 90리터의 메틸에틸 케톤(methylethyl ketone)을 넣은 다음, 단계 (i)에서 설명된 프로세스에 의해 얻은 9kg의 엘로티닙을 넣었다. 온도를 60-65℃로 올려 고체가 완전히 용해되도록 하였다. 카본 처리를 하였으며, 여과액은 10℃로 냉각하여 결정화된 생성물을 센트리퓨즈한 다음, 케이크를 메틸에틸 케톤으로 워싱하고, 젖은 케이크를 건조하여 엷은 황색 결정성 고체와 같은 5.9kg의 고순도 엘로티닙 베이스를 얻었다.The following purification method was employed to obtain a high purity erlotinib base. 90 liters of methylethyl ketone were placed in a clean and dry All Glass Reactor followed by 9 kg of erlotinib obtained by the process described in step (i). The temperature was raised to 60-65 ° C. to allow the solids to dissolve completely. Carbonized, the filtrate was cooled to 10 ° C. to centrifuse the crystallized product, then the cake was washed with methylethyl ketone, and the wet cake was dried to give a 5.9 kg of high purity erlotinib base as a pale yellow crystalline solid. Got.

순도: 99.74% (HPLC에 의해 측정)Purity: 99.74% (measured by HPLC)

녹는 범위(Melting range): 154-155℃Melting range: 154-155 ℃

(iii) 엘로티닙 하이드로클로라이드, 다형체-P의 제조(iii) Preparation of Erlotinib Hydrochloride, Polymorph-P

깨끗하고, 건조된 올글라스 반응기에 110 리터의 메틸렌 클로라이드를 채운 다음, 위 단계 (ii)에서 얻은 바와 같은 5.5kg의 엘로티닙 베이스를 넣었다. 온도를 37±±로 올려, 고체가 완전히 용해되도록 하였다. 이것에 카본 처리하였으며, 여과액은 다른 깨끗하고 건조된 올글라스 반응기로 옮겼다. 이 반응 매스에 이소프로포놀 HCl(isoproponolic HCl; 100% HCl 함량이 0.6371 kg)을 25-35℃에서 1로트(lot)로 첨가한 다음, 반응을 리플럭스 조건에서 3시간 동안 유지시켰다. 반응 매스는 실온으로 냉각하여, 센트리퓨즈하였다. 생성된 케이크는 메틸렌 클로라이드로 워싱하고, 건조하여 백색 결정성 분말과 같은 5.5kg의 엘로티닙 하이드로클로라이드를 얻었다.A clean, dried oliglas reactor was charged with 110 liters of methylene chloride and then 5.5 kg of erlotinib base as obtained in step (ii) above. The temperature was raised to 37 ±± allowing the solids to dissolve completely. It was carburized and the filtrate was transferred to another clean, dry glass reactor. Isoproponolic HCl (0.6371 kg of 100% HCl content) was added to this reaction mass in 1 lot at 25-35 ° C., and then the reaction was maintained under reflux conditions for 3 hours. The reaction mass was cooled to room temperature and centrifuged. The resulting cake was washed with methylene chloride and dried to yield 5.5 kg of erlotinib hydrochloride like white crystalline powder.

순도: 99.82% (HPLC에 의해 측정)Purity: 99.82% (measured by HPLC)

XRPD: 형체-P (도 3과 동일)XRPD: Shape-P (same as Figure 3)

본 발명의 유리한 효과Advantageous Effects of the Invention

1) 엘로티닙 하이드로클로라이드의 신규한 다형체, 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)은 용이하고 제조될 수 있으며, 실온(30-35℃)에서 뿐 아니라 60-120℃와 같은 상승된 온도에서도 매우 안정하다.1) Novel polymorphs, Form-M, Form-N and Form-P of erlotinib hydrochloride are easy and can be prepared, and at room temperature (30- 35 ° C.) as well as very stable at elevated temperatures such as 60-120 ° C.

2) 신규한 다형체, 형체-M(Form-M), 형체-N(Form- N) 및 형체-P(Form-P)은 이소프로판올, 메탄올 및 메틸렌 클로라이드와 같은 저렴한 용매 중에서 제조될 수 있으며, 제조 레벨까지 용이하게 규모를 늘릴 수 있다(scaled-up).2) The novel polymorphs, Form-M, Form-N and Form-P can be prepared in inexpensive solvents such as isopropanol, methanol and methylene chloride, It can be easily scaled up to the manufacturing level.

3) 엘로티닙 하이드로클로라이드의 신규한 다형체, 형체-M(Form-M), 형체-N(Form-N) 및 형체-P(Form-P)을 제조하는 방법은 지속적으로 재생 가능(reproducible)하다.3) Processes for producing novel polymorphs, Form-M, Form-N and Form-P of erlotinib hydrochloride are continuously reproducible Do.

4) 엘로티닙 하이드로클로라이드의 신규한 다형체, 형체-M(Form-M), 형체-N(Form-N) 및 형체-P(Form-P)은 기타 번거로운 크로마토그래피법(chromatographic methods)들이 아닌, 결정화 기술에 의해 정제된 엘로티닙 베이스로부터 제조된다.4) The new polymorphs, Form-M, Form-N, and Form-P of erlotinib hydrochloride are not other cumbersome chromatographic methods. It is prepared from erlotinib base purified by crystallization technique.

Claims (15)

각도 2-쎄타(2-theta)에서 약 6.2, 7.9, 9.6, 11.4, 12.5, 13.4, 14.7,15.7,17.0,17.6, 19.2, 20.2, 20.7, 21.1, 21.9, 22.4, 23.0, 23.9, 24.4, 25.1, 25.9, 26.8, 29.0, 29.7, 31.7, 32.7, 34.8, 40.2로 표시되는 특징적 피크를 가지는 x-레이 분말 회절 패턴(x-ray powder diffraction pattern)을 특징으로 하는 형체-M(Form-M)으로 지정된 N-(3-에티닐페닐)6,7-비스(2-메톡시 에톡시)-4-퀴나졸린아민(N-(3- ethynylphenyl)6,7-bis(2-methoxy ethoxy)-4-quinazolinamine) 하이드로클로라이드 염(hydrochloride salt)의 안정한 신규 결정성 다형체(crystalline polymorph).6.2, 7.9, 9.6, 11.4, 12.5, 13.4, 14.7, 15.7, 17.0, 17.6, 19.2, 20.2, 20.7, 21.1, 21.9, 22.4, 23.0, 23.9, 24.4, 25.1 at an angle 2-theta Form-M, characterized by an x-ray powder diffraction pattern with characteristic peaks represented by 25.9, 26.8, 29.0, 29.7, 31.7, 32.7, 34.8, and 40.2. N- (3-ethynylphenyl) 6,7-bis (2-methoxy ethoxy) -4-quinazolinamine (N- (3-ethynylphenyl) 6,7-bis (2-methoxy ethoxy) -4 Stable new crystalline polymorph of quinazolinamine hydrochloride salt. 제 1 항에 있어서, The method of claim 1, 상기 결정성 다형체는 도 1에 나타나 있는 x-레이 분말 회절 패턴을 특징으로 하는 결정성 다형체.The crystalline polymorph is a crystalline polymorph characterized by the x-ray powder diffraction pattern shown in FIG. 각도 2-쎄타(2-theta)에서 약 5.56, 9.72, 11.25, 12.82, 18.84, 19.38, 21.01, 22.74, 23.46, 24.23, 25.34, 26.70, 29.17, 32.77, 37.21, 39.96, 45.66로 표시되는 특징적 피크를 가지는 x-레이 분말 회절 패턴(x-ray powder diffraction pattern)을 특징으로 하는 형체-N(Form-N)으로 지정된 N-(3-에티닐페닐)6,7-비스(2-메톡시 에톡시)-4-퀴나졸린아민(N-(3-ethynylphenyl)6,7-bis(2-methoxy ethoxy)-4-quinazolinamine) 하이드로클로라이드 염(hydrochloride salt)의 안정한 신규 결정성 다형체(crystalline polymorph).Characteristic peaks represented by about 5.56, 9.72, 11.25, 12.82, 18.84, 19.38, 21.01, 22.74, 23.46, 24.23, 25.34, 26.70, 29.17, 32.77, 37.21, 39.96, 45.66 at an angle 2-theta. Branches are N- (3-ethynylphenyl) 6,7-bis (2-methoxy ethoxy, designated as Form-N), characterized by an x-ray powder diffraction pattern. Stable novel crystalline polymorph of N- (3-ethynylphenyl) 6,7-bis (2-methoxy ethoxy) -4-quinazolinamine) hydrochloride salt. 제 3 항에 있어서, The method of claim 3, wherein 상기 결정성 다형체는 도 2에 나타나 있는 x-레이 분말 회절 패턴을 특징으로 하는 결정성 다형체.The crystalline polymorph is a crystalline polymorph characterized by the x-ray powder diffraction pattern shown in FIG. 각도 2-쎄타(2-theta)에서 약 2.97, 5.80, 6.36, 9.97, 10.54, 11.48, 15.00, 15.80, 16.64, 17.11, 17.62, 18.15, 18.58, 19.06, 19.78, 20.74, 22.14, 22.96, 23.72, 24.45, 25.67, 26.40, 27.30, 28.14, 28.76, 29.44, 30.15, 30.82, 32.21, 32.95, 33.99, 34.59, 40.49, 40.64, 42.02, 43.87로 표시되는 특징적 피크를 가지는 x-레이 분말 회절 패턴(x-ray powder diffraction pattern)을 특징으로 하는 형체- P(Form- P)로 지정된 N-(3-에티닐페닐)6,7-비스(2-메톡시 에톡시)-4-퀴나졸린아민(N-(3-ethynylphenyl)6,7-bis(2-methoxy ethoxy)-4-quinazolinamine) 하이드로클로라이드 염(hydrochloride salt)의 안정한 신규 결정성 다형체(crystalline polymorph).At angle 2-theta, about 2.97, 5.80, 6.36, 9.97, 10.54, 11.48, 15.00, 15.80, 16.64, 17.11, 17.62, 18.15, 18.58, 19.06, 19.78, 20.74, 22.14, 22.96, 23.72, 24.45 X-ray powder diffraction pattern (x-ray powder) with characteristic peaks represented by, 25.67, 26.40, 27.30, 28.14, 28.76, 29.44, 30.15, 30.82, 32.21, 32.95, 33.99, 34.59, 40.49, 40.64, 42.02, 43.87 N- (3-ethynylphenyl) 6,7-bis (2-methoxy ethoxy) -4-quinazolinamine (N- (3), designated as P-Form-P, characterized by a diffraction pattern) Stable new crystalline polymorph of -ethynylphenyl) 6,7-bis (2-methoxy ethoxy) -4-quinazolinamine) hydrochloride salt. 제 5 항에 있어서, The method of claim 5, wherein 상기 결정성 다형체는 도 3에 나타나 있는 x-레이 분말 회절 패턴을 특징으로 하는 결정성 다형체.The crystalline polymorph is a crystalline polymorph characterized by the x-ray powder diffraction pattern shown in FIG. 드라이 메탄올(dry methanol)에 N-(3-에티닐페닐)6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민(N-(3-ethynylphenyl)6,7-bis(2-methoxyethoxy)-4-quinazolinamine) 또는 엘로니팁 베이스(Erlotinib base)를 용해하고, 메탄올 또는 이소프로판올 중 드라이 하이드로클로라이드 가스 용액과 반응시키는 것을 포함하는 제 1 항 또는 제 2 항에 정의된 결정성 다형체 형체-M의 제조방법.N- (3-ethynylphenyl) 6,7-bis (2-methoxyethoxy) -4-quinazolinamine (N- (3-ethynylphenyl) 6,7-bis (2) in dry methanol crystalline polymorph form as defined in claim 1 or 2 comprising dissolving -methoxyethoxy) -4-quinazolinamine) or Erlotinib base and reacting with a dry hydrochloride gas solution in methanol or isopropanol. Preparation of -M. 드라이 이소프로판올(dry isopropanol)에 N-(3-에티닐페닐)6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민(N-(3-ethynylphenyl)6,7-bis(2-methoxyethoxy)-4-quinazolinamine) 또는 엘로니팁 베이스(Erlotinib base)를 용해하고, 이소프로판올 중 드라이 하이드로클로라이드 가스 용액과 반응시키는 것을 포함하는 제 3 항 또는 제 4 항에 정의된 결정성 다형체 형체-M의 제조방법.N- (3-ethynylphenyl) 6,7-bis (2-methoxyethoxy) -4-quinazolinamine (N- (3-ethynylphenyl) 6,7-bis (2) in dry isopropanol crystalline polymorph form M as defined in claim 3 or 4 comprising dissolving -methoxyethoxy) -4-quinazolinamine) or Erlotinib base and reacting with a dry hydrochloride gas solution in isopropanol. Manufacturing method. 드라이 메틸렌 클로라이드(methylene chloride)에 N-(3-에티닐페닐)6,7-비스(2-메톡시에톡시)-4-퀴나졸린아민(N-(3-ethynylphenyl)6,7-bis(2-methoxyethoxy)-4-quinazolinamine) 또는 엘로니팁 베이스(Erlotinib base)를 용해하고, 메탄올 또는 이소프로판올 중 드라이 하이드로클로라이드 가스 용액과 반응시키는 것을 포함하는 제 5 항 또는 제 6 항에 정의된 결정성 다형체 형체-M의 제조방법.N- (3-ethynylphenyl) 6,7-bis (2-methoxyethoxy) -4-quinazolinamine (N- (3-ethynylphenyl) 6,7-bis in dry methylene chloride Crystalline polymorph as defined in claim 5 or 6 comprising dissolving 2-methoxyethoxy) -4-quinazolinamine) or Erlotinib base and reacting with a dry hydrochloride gas solution in methanol or isopropanol. Method for preparing Form-M. 제 1 항 또는 제 2 항에 정의된 엘로티닙 하이드로클로라이드(Erlotinib Hydrochloride)의 안정한 신규 결정성 형체-M 및 약제학적으로 허용 가능한 담체 및/또는 보조제(adjuvant)를 포함하는 항암 활성용 약학적 조성물.A pharmaceutical composition for anticancer activity comprising a stable novel crystalline form-M of erlotinib hydrochloride as defined in claim 1 or 2 and a pharmaceutically acceptable carrier and / or adjuvant. 제 3 항 또는 제 4 항에 정의된 엘로티닙 하이드로클로라이드(Erlotinib Hydrochloride)의 안정한 신규 결정성 형체-N 및 약제학적으로 허용 가능한 담체 및/또는 보조제(adjuvant)를 포함하는 항암 활성용 약학적 조성물.A pharmaceutical composition for anticancer activity comprising a stable novel crystalline form-N of erlotinib hydrochloride as defined in claim 3 or 4 and a pharmaceutically acceptable carrier and / or adjuvant. 제 5 항 또는 제 6 항에 정의된 엘로티닙 하이드로클로라이드(Erlotinib Hydrochloride)의 안정한 신규 결정성 형체-P 및 약제학적으로 허용 가능한 담체 및/또는 보조제(adjuvant)를 포함하는 항암 활성용 약학적 조성물.A pharmaceutical composition for anticancer activity comprising a stable novel crystalline form-P of Erlotinib Hydrochloride as defined in claim 5 or 6 and a pharmaceutically acceptable carrier and / or adjuvant. 실질적으로 실시예-1을 참조하여 설명된 앞서 언급된 특징으로 가지는 제 1 항 또는 제 2 항에 따른 화학식 1의 엘로티닙 하이드로클로라이드의 안정한 신규 결정성 형체-M의 제조방법. A process for the preparation of a stable novel crystalline Form-M of erlotinib hydrochloride of formula 1 according to claim 1 having substantially the aforementioned features described with reference to Example-1. 실질적으로 실시예-2를 참조하여 설명된 앞서 언급된 특징으로 가지는 제 3 항 또는 제 4 항에 따른 화학식 1의 엘로티닙 하이드로클로라이드의 안정한 신규 결정성 형체-N의 제조방법. A process for the preparation of a stable novel crystalline form-N of erlotinib hydrochloride of formula (1) according to claim 3 or 4 having substantially the above-mentioned features described with reference to Example-2. 실질적으로 실시예-3 및 4를 참조하여 설명된 앞서 언급된 특징으로 가지는 제 5 항 또는 제 6 항에 따른 화학식 1의 엘로티닙 하이드로클로라이드의 안정한 신규 결정성 형체-P의 제조방법. A process for the preparation of a stable novel crystalline Form-P of erlotinib hydrochloride of formula (I) according to claim 5 or 6 having substantially the aforementioned features described substantially with reference to Examples-3 and 4.
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